Project Summary Patients with schizophrenia, as well as subjects with 22q11.2 deletion, which raises the risk of schizophrenia 30-fold, have pronounced disturbances in cognitive tasks that depend on the hippocampus and prefrontal cortex, including working memory. To clarify the neurobiology underlying these disturbances, we have studied working memory in a mouse model of the 22q11.2 deletion (Df(16)A+/? mice). In the first iteration of this grant, we demonstrated that the deletion results in deficits in axon branching, working memory and neural synchrony in the hippocampal-prefrontal circuit. We further demonstrated that these deficits were at least partially due to haploinsufficiency of the Zdhhc8 gene, which results in the axonal mislocalization of key signaling proteins, including AKT, a negative regulator of the kinase Gsk3. Moreover, consistent with the hypothesis that Zdhhc8 deficiency may affect working memory and hippocampal-prefrontal HPC-PFC synchrony via hyperactivity of Gsk3 signaling, we found that developmental Gsk3 inhibition reversed deficits in spatial working memory task acquisition, neural synchrony and prefrontal representations of goal information in Df(16)A+/? mice. Building on these findings, this competitive renewal proposes to (1) Determine when during the lifespan (postnatal, adolescent and adult time periods) Gsk3 antagonism is most effective at reversing physiological and behavioral deficits (2) Test whether isoform-specific Gsk3 (? or ?) antagonists can reverse working memory- related phenotypes in Df(16)A+/? mice, using recently developed investigational drugs more suitable for future clinical trials, aimed specifically at either isoform and (3) confirm the causal role of hippocampal-prefrontal synchrony in working memory deficits by manipulating synchrony physiologically using state-of-the-art approaches established in the course of this grant and measuring the resultant effects on working memory behavior in wild-type and 22q11.2 model mice. The proposed experiments serve both basic and translational goals. From the basic perspective, they will clarify the causal relationship between a specific circuit (the hippocampal-prefrontal circuit) and a well-characterized behavior (spatial working memory) while simultaneously clarifying the molecular and physiological substrates for plasticity within the system, both during development and in the adult. From the translational perspective, they will help guide the development of therapies aimed at manipulating this system, including pharmacological and/or brain stimulation treatments, and help define whether such treatments might be efficacious in affected adults, or should be targeted to earlier time points in highly susceptible individuals.